clomiPRAMINE (Monograph)

Brand name: Anafranil
Drug class: Tricyclics and Other Norepinephrine-reuptake Inhibitors
VA class: CN601
Chemical name: 3-Chloro-10,11-dihydro-N,N-dimethyl -5H-dibenz[b,f]azepine-5-propanamine monohydrochloride
Molecular formula: C₁₉H₂₃ClN₂•HCl
CAS number: 17321-77-6

Medically reviewed by Drugs.com on May 22, 2024. Written by ASHP.

Warning

Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (18–24 years of age) with major depressive disorder and other psychiatric disorders; balance this risk with clinical need.^d ^e Clomipramine is not approved for use in pediatric patients except patients with obsessive-compulsive disorder.¹ (See Pediatric Use under Cautions.)
In pooled data analyses, risk of suicidality was not increased in adults >24 years of age and apparently was reduced in adults ≥65 years of age with antidepressant therapy compared with placebo.^d ^e
Depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide.^d ^e ^f
Appropriately monitor and closely observe all patients who are started on clomipramine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process.^d ^e ^f (See Worsening of Depression and Suicidality Risk under Cautions.)

Introduction

Tricyclic antidepressant (TCA);¹ ² ³ ²³⁵ pharmacologic profile resembles that of other TCAs,²³⁵ ²³⁸ SSRIs, and trazodone.² ³ ⁴ ²¹² ²¹³ ²¹⁴ ²²⁰ ²²¹

Uses for clomiPRAMINE

Obsessive-Compulsive Disorder (OCD)

Among the drugs of choice for the management of OCD.⁶⁹ ²⁸⁹ ²⁹³ ²⁹⁶ ²⁹⁷

Reduces but does not completely eliminate obsessions and compulsions.⁹⁶ ²⁷¹ ²⁹² ³⁰⁰

Panic Disorder

Has been used effectively for the management of panic disorder^{† [off-label]} with or without agoraphobia^{† [off-label]}.² ³ ⁴ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹⁰⁹ ¹¹⁰ ¹¹⁶ ³⁴⁷

Major Depressive Disorder

Has been used effectively for the management of major depressive disorder^{† [off-label]}.² ³ ²⁵⁴ ²⁵⁵ ²⁵⁶ ²⁵⁷ ²⁵⁸ ²⁵⁹ ²⁶⁰ ²⁶⁷ ²⁷⁷ ²⁷⁸ ²⁸² ²⁸⁸

Despite comparable efficacy,² ³ ²⁵⁵ ²⁵⁶ ²⁵⁷ ²⁵⁸ ²⁶⁰ ²⁷⁷ ²⁸² ²⁸³ the adverse effect profile (e.g., anticholinergic effects) of clomipramine may limit its usefulness relative to other antidepressants (e.g., TCAs, SSRIs).² ²⁵⁷ ²⁵⁸ ²⁷⁷ ²⁸² ²⁸³ ²⁸⁸ ²⁸⁹

Effective antidepressant when obsessive manifestations accompany episode of major depressive disorder.²⁸⁸

Chronic Pain

Has been used for the management of chronic pain^{† [off-label]} (e.g., central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, cancer pain) alone or as adjunct to conventional analgesics.² ³ ⁵² ¹¹¹ ¹¹² ¹¹³ ¹¹⁴ ¹¹⁵ ¹¹⁸ ¹¹⁹ ¹²⁰ ¹²¹ ¹²² ¹²³ ¹²⁴ ¹²⁵ ³⁴³ ³⁴⁴

Cataplexy and Associated Narcolepsy

Has been used for the symptomatic management of cataplexy^{† [off-label]} in a limited number of patients with cataplexy^† and associated narcolepsy^†.³ ¹³² ¹³³ ²⁷⁹

Autistic Disorder

Has been used for the management of repetitive and obsessive-compulsive behaviors and hyperactivity associated with autistic disorder^†;¹³⁴ ¹³⁵ ¹⁴¹ ²⁸⁵ ²⁸⁶ does not treat core symptoms of autistic disorder.^b

Trichotillomania

Has been used for the management of trichotillomania^† (an urge to pull out one’s hair) in a limited number of patients with the disorder;³ ¹³⁶ ¹³⁷ ¹³⁸ ¹³⁹ relapse reported in some patients receiving long-term therapy.¹⁴⁰

Onychophagia

Has been used for the management of severe onychophagia^† (nail biting) without a history of OCD.¹⁴²

Associated with relatively high dropout rate because of adverse effects and drug intolerance; not considered first-line therapy in most patients with onychophagia.¹⁴² ³⁴¹

Eating Disorders

Has been used for the management of anorexia nervosa^† in a limited number of patients with the disorder.²²⁹ ²³⁰ ²³¹

Initial therapeutic effects (e.g., improved eating behavior, weight gain) not sustained with long-term therapy (e.g., ≥8 weeks).²²⁹ ²³⁰ ²³¹ ²³⁴

Avoid use in underweight individuals and in those exhibiting suicidal ideation.²⁸⁸ ³⁴¹

Premature Ejaculation

Has been used for the management of premature ejaculation^†.³ ¹²⁸ ¹²⁹ ¹³⁰ ¹³¹

Premenstrual Syndrome

Has been used for the management of premenstrual syndrome^†.²⁶¹ ²⁶² ²⁶³ ²⁶⁴

clomiPRAMINE Dosage and Administration

General

Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of clomipramine and vice versa.¹ Also allow at least 5 weeks to elapse when switching from fluoxetine.¹
Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.^d ^e ^f (See Worsening of Depression and Suicidality Risk under Cautions.)
Sustained therapy may be required;² ⁴ ³³ ⁷⁸ ⁸⁰ ⁸¹ ⁸² ¹⁴⁸ ³⁴¹ use lowest effective dosage and monitor periodically for need for continued therapy.¹ ²⁹⁹
Avoid abrupt discontinuance of therapy.¹ ² ⁷⁸ ¹⁴⁸ ³⁰¹ To avoid withdrawal reactions, taper dosage gradually (e.g., over a period of approximately 2 weeks).¹ ² ⁷⁸ ¹⁴⁸ ³⁰¹

Panic Disorder†

Transient increase in the number and intensity of panic attacks may occur during initial therapy with the drug.⁴ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ²⁸⁸

Administration

Oral Administration

Administer orally; initially, in divided doses with meals to lessen adverse GI effects.¹ After initial dosage titration, the total daily dose may be given once daily at bedtime¹ ² ⁴ ²⁷¹ to minimize adverse effects (e.g., sedation) during waking hours¹ ² and enhance patient compliance.²

Also has been administered IM^† or IV^†, but a parenteral dosage form is not commercially available in the US.⁴ ²⁷²

Dosage

Available as clomipramine hydrochloride; dosage is expressed in terms of the salt.¹

Individualize dosage carefully according to individual requirements and response.¹

Allow 2–3 weeks to elapse between any further dosage adjustments after the initial dosage titration period for achievement of steady-state plasma concentrations.¹

Pediatric Patients

OCD

Oral

Children >10 years of age: initially, 25 mg daily.¹ Gradually increase dosage, as tolerated, during the first 2 weeks of therapy up to a maximum of 3 mg/kg or 100 mg daily, whichever is lower.¹ ² ²⁴² Titrate dosage carefully.¹ If necessary, dosages may be increased gradually during the next several weeks up to a maximum of 3 mg/kg or 200 mg daily (whichever is lower).¹ ² ³ ⁴ ⁶⁶ ⁶⁷

Optimum duration not established; ¹ ⁷⁸ ²⁷¹ some clinicians recommend that therapy be continued in responding patients at the minimally effective dosage for at least 18 months before attempting to discontinue.¹ ²⁷¹ ²⁹⁹

Adults

OCD

Oral

Initially, 25 mg daily.¹ Gradually increase dosage, as tolerated, during the first 2 weeks of therapy to approximately 100 mg daily.¹ If necessary, dosages may be increased gradually during the next several weeks up to a maximum of 250 mg daily.¹ ² ³ ⁴ ⁶⁶ ⁶⁷

Panic Disorder†

Oral

Usual dosage: ≤50 mg daily (range: 12.5–150 mg daily);² ⁴ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹¹⁰ ¹¹⁶ ²⁷² patients with agoraphobia may require higher dosage.⁴ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶

Major Depressive Disorder†

Oral

100–250 mg daily.² ²⁷² ²⁷⁷ ²⁷⁸ ²⁸⁸

Chronic Pain†

Oral

100–250 mg daily.² ¹¹⁵ ²⁷² ²⁸⁸

Cataplexy and Associated Narcolepsy†

Oral

25–200 mg daily.¹³² ¹³³ ²⁷² ²⁷⁹

Prescribing Limits

Pediatric Patients

OCD

Oral

Maximum 3 mg/kg or 200 mg daily, whichever is lower.¹ ² ³ ⁴ ⁶⁶ ⁶⁷

Adults

OCD

Oral

Maximum 250 mg daily.¹ ² ³ ⁴ ⁶⁶ ⁶⁷

Panic Disorder†

Oral

Maximum 200 mg daily.² ⁴ ¹⁰⁴ ¹⁰⁵ ¹⁰⁶ ¹⁰⁷ ¹⁰⁸ ¹¹⁰ ¹¹⁶ ²⁷²

Special Populations

Geriatric Patients

Manufacturer makes no specific recommendation for dosage adjustment¹ ⁴¹ ²⁴⁰ but lower clomipramine hydrochloride dosages are recommended by some clinicians at least during initial therapy.² ⁴ ²⁷² ²⁸²

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹

Cautions for clomiPRAMINE

Contraindications

Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor.¹ (See Specific Drugs under Interactions.)
During the acute recovery phase following MI.¹
Known hypersensitivity to clomipramine or other TCAs.¹

Warnings/Precautions

Warnings

Seizures

Risk of seizure; use with caution in patients with a history of seizures or other predisposing factors (e.g., brain damage of various etiology, alcoholism, concurrent use of other drugs that lower the seizure threshold).¹

Risk may be dose related.¹ (See Prescribing Limits under Dosage and Administration.)

Worsening of Depression and Suicidality Risk

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients, whether or not they are taking antidepressants; may persist until clinically important remission occurs.^d ^e ^f ^g However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.^d ^e ^f

Appropriately monitor and closely observe patients receiving clomipramine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.^d ^e ^f (See Boxed Warning and also see Pediatric Use under Cautions.)

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.^e ^f Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or not part of patient’s presenting symptoms.^d ^e ^f (See General under Dosage and Administration and also see Withdrawal Reactions under Cautions.)

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.¹ ^e

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, OCD) or nonpsychiatric disorders.^e

Bipolar Disorder

May unmask bipolar disorder.^e (See Activation of Mania or Hypomania under Cautions.) Clomipramine is not approved for use in treating bipolar depression.¹

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.^e

General Precautions

Cardiovascular Effects

Modest orthostatic decreases in BP,¹ ¹⁹³ modest tachycardia,¹ and/or ECG abnormalities (e.g., VPCs, ST-T wave changes, intraventricular conduction abnormalities) reported; use with caution in patients with known cardiovascular disease.¹

Titrate dosage carefully.¹

Neuropsychiatric Effects

Variety of neuropsychiatric manifestations (e.g., delusions, hallucinations, psychotic episodes, confusion, paranoia) reported.¹ ³ ¹⁵⁵ ¹⁵⁶ ²³⁸

May precipitate an acute psychotic episode in patients with unrecognized schizophrenia.¹ ³ ¹⁵⁵ ¹⁵⁶ ²⁹⁵

Activation of Mania or Hypomania

Risk of activation of mania or hypomania in patients with affective disorder.¹ ³ ¹⁵⁵ ¹⁵⁶ ²⁹⁵ (See Bipolar Disorder under Cautions.)

Anticholinergic Effects

Use with caution in patients for whom excess anticholinergic activity could be harmful (e.g., history of urinary retention, increased intraocular pressure, angle-closure glaucoma).¹

Interactions

More than 30 cases of hyperthermia reported,¹ most cases occurring in patients receiving clomipramine in combination with other drugs (e.g., antipsychotic agents).¹ ¹⁵⁷ ¹⁹⁹ When clomipramine and an antipsychotic agent were used concomitantly, the cases sometimes were considered to be examples of neuroleptic malignant syndrome (NMS).¹ ¹⁵⁷ ¹⁹⁹

Hepatic Effects

Potentially clinically important elevations (e.g., >3 times ULN) in serum ALT¹ ⁶⁵ and AST¹ concentrations;¹ severe hepatic injury and/or death rarely reported.¹

Possible cross hepatotoxicity (e.g., elevated values on hepatic function tests, abdominal pain) involving different TCAs including clomipramine.²⁰⁷ (See Hepatic Impairment under Cautions.)

Hematologic Effects

Bone marrow depression¹ ²²⁷ (e.g., leukopenia,¹ agranulocytosis,¹ ³ ¹⁶² ¹⁶⁴ ¹⁶⁵ ¹⁶⁶ thrombocytopenia,¹ anemia,¹ pancytopenia)¹ ³ ¹⁶³ rarely reported.¹ ²²⁷

Obtain leukocyte and differential blood cell counts if fever and sore throat occur during therapy.¹

Sexual Dysfunction

Relatively high risk of sexual dysfunction¹ ³ ¹⁸⁰ (e.g., libido change,¹ ⁶⁵ ¹⁸⁹ ²⁵¹ ejaculatory failure,¹ ⁶⁵ ¹⁸⁰ ¹⁸⁸ ²⁵¹ impotence¹ ⁶⁵ ¹⁸⁹ ²⁴⁵ ²⁷⁰ ) in male patients with OCD.¹

Normal sexual functioning usually returns within a few days after discontinuing therapy.² ³ ¹⁸⁰

Weight Changes

Possible weight gain¹ ²⁴² ²⁴⁵ ²⁴⁷ ²⁴⁹ or weight loss.¹

Withdrawal Reactions

Withdrawal reactions (e.g., dizziness, nausea, vomiting, headache, malaise, sleep disturbance, hyperthermia, sweating, irritability, seizures, worsening of psychiatric status) reported following abrupt discontinuance of therapy.¹ ² ⁷⁸ ¹⁴⁸ ³⁰¹

To avoid withdrawal reactions, taper dosage gradually and monitor patients carefully.¹ ² ⁷⁸ ¹⁴⁸ ³⁰¹

Electroconvulsive Therapy (ECT)

Possible increased ECT risks; limit to patients for whom concomitant use is essential.¹

Elective Surgery

Discontinue therapy for as long as is clinically feasible prior to surgery and advise the anesthetist of such action.¹

Thyroid Disease

Use with caution in hyperthyroid patients or patients receiving thyroid agents because of the possibility of cardiac toxicity.¹ ¹

Adrenal Medulla Tumors

Use with caution in patients with tumors of the adrenal medulla, in whom hypertensive crises may be provoked.¹

Specific Populations

Pregnancy

Category C.¹

Possible withdrawal symptoms (e.g., jitteriness,¹ ⁷¹ ¹⁵² ¹⁵⁸ tremor,¹ ⁷¹ ¹⁵³ ¹⁵⁴ seizures¹ ³ ¹⁵² ¹⁵³ ) in neonates whose mothers received clomipramine throughout pregnancy;¹ avoid use during late pregnancy whenever possible.¹⁵³

Lactation

Distributed into milk;¹ ⁴ ²² ⁵⁵ ⁶⁰ ⁶² ⁷¹ ¹⁵⁰ discontinue nursing or the drug.¹ ⁶² ¹⁴⁹ ¹⁵⁰ ¹⁵¹

Pediatric Use

Safety and efficacy for OCD not established in children <10 years of age.¹

Potential risks associated with long-term use (e.g., effects on growth, development, or maturation) not systematically evaluated in children and adolescents.¹

Adverse effects in children and adolescents >10 years of age generally similar to those in adults.¹

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, OCD, or other psychiatric disorders based on pooled analyses of 24 short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others).^e However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.^g No suicides occurred in these pediatric trials.^e ^g

Carefully consider these findings when assessing potential benefits and risks of clomipramine in a child or adolescent for any clinical use.^d ^e ^f ^g (See Worsening of Depression and Suicidality Risk under Cautions.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.^d ^e (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

Possible increased sensitivity to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotension, and sedative effects of TCAs.^h ⁱ ^j ^k

Hepatic Impairment

Use with caution in patients with clinically important hepatic disease; periodically monitor hepatic enzyme concentrations.¹

Renal Impairment

Use with caution in patients with clinically important renal impairment.¹

Common Adverse Effects

Adverse GI (e.g., dry mouth, constipation, nausea, dyspepsia, anorexia, increased appetite), nervous system (e.g., somnolence, tremor, dizziness, nervousness, fatigue, myoclonus), or genitourinary (e.g., changed libido, ejaculatory failure, impotence, micturition disorder) effects; sweating; weight gain; visual changes.¹ ² ³⁵ ⁶⁵ ²⁴²

Drug Interactions

Extensively metabolized in the liver by various CYP isoenzymes (e.g., CYP1A2,³⁴⁶ CYP2C,⁷³ CYP2D6,⁷² ⁷³ CYP3A4).^c

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6 and/or 1A2: Potential pharmacokinetic interaction (increased plasma clomipramine concentrations).^a Monitor plasma clomipramine concentrations whenever a CYP2D6 inhibitor is added or discontinued and adjust dosages as needed.^a

Drugs Associated with Serotonin Syndrome

Potential pharmacologic (serotonin syndrome) interaction with serotonergic agents.¹ ¹⁷⁵ ³⁰² ³⁰³ Avoid such use whenever clinically possible.¹ ³⁰² ³⁰³

Drugs Affecting the Seizure Threshold

Use caution with concurrent administration of clomipramine and drugs (e.g., other antidepressants, antipsychotic agents) that lower the seizure threshold.¹

Protein-bound Drugs

Potential for clomipramine to displace or to be displaced by other protein-bound drugs.¹ Observe patients for adverse effects.¹ ²

Specific Drugs

Drug	Interaction	Comments
Alcohol	Potential for increased CNS effects of alcohol¹ Limited data suggest that demethylation of clomipramine may be reduced with chronic alcohol consumption⁵⁵ ⁶⁰ ⁶³ ⁶⁴	Advise patients of risks of such concomitant use¹
Alprazolam	Adverse effects resembling serotonin syndrome¹⁷⁴ ¹⁷⁸
Antiarrhythmics: class 1C (e.g., flecainide, propafenone)	Potential for decreased clomipramine metabolism^a	Monitor for TCA toxicity^a
Anticholinergic agents	Potential for additive anticholinergic effects¹ ² ^c	Use with caution; dosage adjustment may be needed¹ ² ^c
Antipsychotic agents (e.g., phenothiazines)	Hyperthermia and adverse effects resembling NMS¹ ¹⁵⁷ ¹⁹⁹ Potential for decreased clomipramine metabolism^c	Dosage adjustment may be needed^c
Barbiturates (e.g., phenobarbital)	May be additive with or may potentiate CNS effects¹ ¹⁵⁹ Possible decreased plasma clomipramine concentrations¹ ¹⁵⁹ Increased plasma phenobarbital concentrations reported¹	Advise patients of risks associated with such concomitant use¹
Cimetidine	Potential increased plasma clomipramine concentrations¹ ¹⁵⁹ ^c	Use with caution; dosage adjustment may be needed^c
CNS depressants (e.g., alcohol, sedatives, hypnotics)	Potentiates effects of CNS depressants¹ ^c	Use with caution^c
Digoxin	Possible altered protein binding of clomipramine or digoxin¹ ²	Monitor for adverse effects¹ ²
Haloperidol	Potential for increased plasma clomipramine concentrations¹ ²	Use with caution; dosage adjustment may be needed^c
Hypotensive agents (e.g., clonidine, guanethidine)	May antagonize antihypertensive effects¹ ² ¹⁵⁹	Monitor BP^c
Levodopa	May interfere with levodopa absorption^c	Monitor levodopa dosage carefully^c
Lithium	Adverse effects resembling serotonin syndrome¹⁷⁴ ¹⁷⁸
MAO inhibitors (e.g., phenelzine)	Potentially life-threatening serotonin syndrome¹ ² ¹⁵⁹ ¹⁶⁰ Status epilepticus reported with concomitant phenelzine use² ³ ¹⁶¹	Concomitant use contraindicated¹ ^c Allow at least 14 days to elapse when switching to or from these drugs¹ ^c
Methylphenidate	Possible increased plasma clomipramine concentrations¹ ¹⁵⁹
Oral contraceptives	No evidence of interference with clomipramine therapeutic effects¹⁵⁹
Phenytoin	Possible decreased plasma clomipramine concentrations¹ ¹⁵⁹
SSRIs (e.g., fluoxetine, fluvoxamine)	Possible serotonin syndrome^c Potential decreased clomipramine metabolism and increased plasma concentrations^a ^c Possible seizures with concomitant fluoxetine use¹⁷⁰ Severalfold elevation of plasma clomipramine concentration with concomitant fluvoxamine use¹⁷¹	Use with caution;^c monitor for TCA toxicity^a Allow at least 5 weeks to elapse when switching from fluoxetine^a ^c
Smoking	Possible decreased plasma clomipramine concentrations¹ ² ⁴¹ ⁵⁵ ⁶⁰
Sympathomimetic agents (e.g., amphetamines, epinephrine, isoproterenol, norepinephrine, phenylephrine)	Increased vasopressor, cardiac effects^c	Use with caution; dosage adjustment may be required^c
Thyroid agents (e.g., levothyroxine, liothyronine)	May accelerate the onset of therapeutic effects of TCA^c Possible cardiac arrhythmias^c	Use with caution^c
Valproic acid	Possible elevated serum clomipramine concentrations; may precipitate seizures in predisposed individuals²⁹⁸
Warfarin	Possible altered protein binding of clomipramine or warfarin¹ ²	Monitor for adverse effects¹ ²

clomiPRAMINE Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration,² ³ ⁴ ⁵ ¹⁰ ⁵⁵ with peak plasma concentrations usually attained within 2–6 hours (mean: 4.7 hours).¹ ¹⁰ ¹¹ ¹² ²⁵ ²⁹

Oral bioavailability is about 50% because of extensive first-pass metabolism.¹ ² ²⁵ ⁵⁵

Onset

Therapeutic response in OCD generally occurs within 2–6 weeks, with maximal effects after 3–4 months.³³ ⁶⁶ ⁹⁹ ¹⁰³

Food

Food does not appear to substantially affect bioavailability from capsules.¹ ²⁹

Special Populations

In geriatric patients, plasma concentrations of clomipramine and its major active metabolite (desmethylclomipramine) are substantially higher than those in younger adults (18–40 years of age).¹ ⁴¹ ⁶⁰

In children <15 years of age, plasma concentration-dose ratios of clomipramine are substantially lower than those of adults.¹ ⁴³

In smokers, steady-state plasma clomipramine concentrations are substantially lower than in nonsmokers;¹ ⁴¹ ⁵⁵ ⁶⁰ smoking appears to have less effect on plasma concentrations of desmethylclomipramine.⁶⁰

Distribution

Extent

Clomipramine and desmethylclomipramine widely distributed in body tissues, with moderate to high concentrations occurring in organs such as the lungs, adrenals, kidneys, heart, and brain.¹ ³ ⁵ ¹⁰ ⁵³

Crosses the blood-brain barrier; desmethylclomipramine concentration in CSF is about 2.6 times higher than in plasma.¹

Crosses the placenta and distributes into milk.¹ ⁴ ²² ⁵⁵ ⁶⁰ ⁶² ⁷¹

Plasma Protein Binding

Approximately 97–98%, principally to albumin and possibly to α₁-acid glycoprotein (α₁-AGP).¹ ² ⁴ ²⁹ ⁵⁵ ⁵⁶

Elimination

Metabolism

Extensively metabolized to active metabolites¹ ² ³ ⁴ ⁵ ¹⁹ ²⁰ ⁵⁵ ⁶¹ ⁷² ⁷³ by various CYP isoenzymes (e.g., CYP1A2,³⁴⁶ CYP2C,⁷³ CYP2D6,⁷² ⁷³ CYP3A4).^c

Exhibits nonlinear pharmacokinetics at dosages >150 mg daily.¹ ⁸ Metabolism of clomipramine and desmethylclomipramine may be capacity limited (saturable).¹ ⁸ ⁵⁵

Elimination Route

Clomipramine and metabolites excreted in urine and in feces (via biliary elimination).¹ ⁴ ⁵ ¹¹ ²¹ ²⁹ ⁵⁵ ⁷³

Half-life

Elimination half-lives of clomipramine and desmethylclomipramine are approximately 32 hours (range: 19–37 hours) and 69 hours (range: 54–77 hours), respectively, after a 150-mg oral dose.¹ ²

Elimination half-lives may be considerably prolonged at dosages near upper limit of recommended dosage range (i.e., 200–250 mg daily).¹ ⁸

Special Populations

Effects of renal and hepatic impairment on the disposition of clomipramine have not been fully elucidated.¹ ⁶⁰

Hemodialysis, peritoneal dialysis, forced diuresis, and/or exchange transfusion are unlikely to remove clomipramine and desmethylclomipramine substantially because of the drug’s rapid distribution into body tissues.¹

Stability

Storage

Oral

Capsules

Tightly closed container at ≤30°C.¹ Protect from moisture.¹

Actions

Mechanism of action in the management of OCD unknown but may involve inhibition of reuptake of serotonin.¹ ² ³ ²¹³ ²¹⁴ ²²⁰
Desmethylclomipramine inhibits norepinephrine reuptake;² ³ ⁴ ⁴⁸ ²¹² ²¹³ ²¹⁴ ²²⁰ ²²¹ ²³⁵ therefore, clomipramine also shares pharmacologic profile of other tricyclic antidepressants.²³⁵ ²³⁸
Exhibits marked anticholinergic activity, which may account for ³ ⁴ ²⁸⁸ ²⁸⁹ sedation,¹ ⁶⁵ ²³⁸ ²⁴² adverse cardiovascular effects,¹ ² ¹⁹³ ²²² ²³⁵ ³³⁹ and reduced seizure threshold (particularly at relatively high dosages).¹ ²¹⁰

Advice to Patients

Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.^d ^e ^f FDA recommends providing written patient information (medication guide) explaining risks of suicidality each time the drug is dispensed.^d ^e ^f
Importance of informing patients about the risk of seizures associated with the drug.¹
Importance of discussing with patients the risk of serious injury to themselves or others resulting from sudden loss of consciousness (e.g., because of seizures) while engaged in certain complex and hazardous activities (e.g., operation of complex machinery, driving a motor vehicle, swimming, climbing).¹
Importance of cautioning patients about the use of alcohol, barbiturates, or other CNS depressants (see Interactions).¹ ²⁴³
Importance of informing male patients about the relatively high incidence of sexual dysfunction associated with the drug.¹ ³ ¹⁸⁰
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹
Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

clomiPRAMINE Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	25 mg*	Anafranil (with parabens)	Mallinckrodt
			clomiPRAMINE Hydrochloride Capsules	Mylan
		50 mg*	Anafranil (with parabens)	Mallinckrodt
			clomiPRAMINE Hydrochloride Capsules	Mylan
		75 mg*	Anafranil (with parabens)	Mallinckrodt
			clomiPRAMINE Hydrochloride Capsules	Mylan

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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